ABSTRACT The increasing rate of obesity has been declared and epidemic by the U.S. Surgeon General. Increase obesity rates lead to an increase in related chronic diseases that have a profoundly negative impact on health worldwide (1). Those include hypertension, type 2 diabetes, cardiovascular diseases, and cancers. Obesity- related conditions cause an estimated 325,000 premature deaths and cost over 150 billion dollars each year in the U.S. alone (2,3). Given the strong link between obesity and serious co-morbidities, developing safe, and effective anti-obesity treatments has become a global priority. Current approached to combat obesity focus on lifestyle changes, weight-loss surgery, and pharmaco-therapy. Dietary and lifestyle changes can be effective but are difficult to maintain long-term. Weight loss surgery is only an option for treating adults and teenagers with severe obesity and related health problems such as type 2 diabetes, and high blood pressure. More importantly, bariatric surgery is invasive, expensive and associated with significant health risks. Most FDA approved pharmacological approaches for treating obesity act on the brain, by suppressing appetite or caloric intake (Table 1) (4). However, these agents have a major history of failure due to adverse side effects and limited efficacy. Current pharmacological approaches do not target the cellular process of producing adipose tissue or regulating fat storage. Thus revealing a critical need for effective pharmacological treatments that ameliorate or reverse the obese phenotype and improve obesity related co-morbidities. We developed a novel protein-based agent, TL-201 that inhibits the Transforming Growth Factor-? (TGF-?) pathways with key roles in adipose tissue development, turnover, homeostasis, or function (5- 11). Our preliminary data shows that TL-201 suppresses new fat cell formation in culture, reduces lipid accumulation in adipocytes, and/or prevents enlargement of fat depots in ovarectomized (OVX) mice in vivo. Tl-201 was developed at Michigan State University in the laboratory of Dr. Erik Martinez-Hackert (12-14). Talapo Therapeutics has obtained an exclusive license to a published patent from Michigan State University, and for two follow-up applications that will be filed in the near future. To evaluate our novel anti-obesity therapeutic, we propose the following Specific Aims: AIM 1. Define role of Talapo agents on body composition and metabolism of mice subjected to high fat diet (HFD). AIM2. Determine safety profile of TL- 201. AIM 3. Validation of TL-201 in human pre-adipocyte differentiation and identification of biomarkers. Successful completion of this project will demonstrate that TL-201 reduces fat deposits in two different animal models. This will lay the foundation for a Phase II study and further therapeutic development.